Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Genetics. 2024 Jan 3;226(1). doi: 10.1093/genetics/iyad202.
Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer's disease (FAD). Studies in cell culture, in vitro biochemical systems, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing γ-secretase activity. Mouse genetic analysis highlighted the importance of Presenilin (PS) in learning and memory, synaptic plasticity and neurotransmitter release, and neuronal survival, and Drosophila studies further demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, molecular pathways that interact with PS in neuronal survival remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new DrosophilaPsn model that exhibits age-dependent neurodegeneration and increases of apoptosis. Following a bioinformatic analysis, we tested top ranked candidate genes by selective knockdown (KD) of each gene in neurons using two independent RNAi lines in Psn KD models. Interestingly, 4 of the 9 genes enhancing neurodegeneration in Psn KD flies are involved in lipid transport and metabolism. Specifically, neuron-specific KD of lipophorin receptors, lpr1 and lpr2, dramatically worsens neurodegeneration in Psn KD flies, and overexpression of lpr1 or lpr2 does not alleviate Psn KD-induced neurodegeneration. Furthermore, lpr1 or lpr2 KD alone also leads to neurodegeneration, increased apoptosis, climbing defects, and shortened lifespan. Lastly, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 similarly lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that LpRs modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.
早发性家族性阿尔茨海默病（FAD）最常见的病因是早老素（PSEN）基因突变。细胞培养、体外生化系统和基因敲入小鼠的研究表明，PSEN 突变是功能丧失性突变，会损害γ-分泌酶的活性。小鼠遗传学分析强调了 Presenilin（PS）在学习和记忆、突触可塑性和神经递质释放以及神经元存活中的重要性，果蝇研究进一步证明了 PS 在衰老过程中对神经元存活的进化保守作用。然而，与 PS 相互作用的分子途径在神经元存活中仍不清楚。为了鉴定调节 PS 依赖性神经元存活的遗传修饰因子，我们开发了一种新的果蝇 Psn 模型，该模型表现出与年龄相关的神经退行性变和凋亡增加。在进行了生物信息学分析之后，我们使用两个独立的 RNAi 系在 Psn KD 模型中对每个基因在神经元中的选择性敲低（KD），测试了排名最高的候选基因。有趣的是，在 Psn KD 果蝇中增强神经退行性变的 9 个候选基因中有 4 个与脂质转运和代谢有关。具体来说，神经元特异性 KD 的脂蛋白受体 lpr1 和 lpr2，显著加重了 Psn KD 果蝇的神经退行性变，而过表达 lpr1 或 lpr2 并不能缓解 Psn KD 诱导的神经退行性变。此外，lpr1 或 lpr2 的单独 KD 也会导致神经退行性变、凋亡增加、攀爬缺陷和寿命缩短。最后，lpr1 和 lpr2 的杂合缺失或 lpr1 或 lpr2 的纯合缺失同样导致与年龄相关的神经退行性变，并进一步加重 Psn KD 果蝇的神经退行性变。这些发现表明 LpRs 调节 Psn 依赖性神经元存活，对衰老大脑中神经元的完整性至关重要。
